​Research Images

A possible approach to inhibition of PR autoprocessing from its Gag-Pol precursor involves disruption of the PR dimer interface. Binding of a monoclonal antibody that recognizes the N-terminal sequence of the mature PR, resulting in its dissociative inhibition, constitutes a proof of this principle. The antibody inhibits cleavage between the PR and RT domains after N-terminal autoprocessing.

The first crystal structures of a precursor mimetic (SFNFPR; four residues derived from the TFR are appended to its N-terminus) reveal several novel conformations, including disengagement of the four N-terminal residues (P1QIT4) from the β-sheet interface, accounting for its markedly lower dimer stability.

Each of the two identical 99-amino acid subunits of PR contributes one of the catalytic Asp25 residues. Interactions that hold the dimer together involve the active site (Asp25 residues shown) and flaps, and the β-sheet comprising the four N-terminal and four C-terminal residues of each monomer. Deletion of the C-terminal residues results in a stable but inactive PR monomer whose residues 10-90 adopt a fold similar to that of the dimer, as revealed by its NMR structure. Precursor with PR flanked by the TFR adopts a similar monomer fold. The N-terminal transframe octapeptide shown in surface representation (cleaved from the TFR at pH < 5; site 2 in figure 1) and its Glu-Asp-Leu sequence are competitive inhibitors of PR. Polar interactions with these residues enable a pH-dependent regulatory mechanism for PR maturation.